A Universal Approach to Personalized Adoptive T cell Therapy of Cancer

描述(申请人提供)：基因工程T淋巴细胞已经成为“现成的”连环杀手，能够在体内识别和根除实体和血液病癌症。表达嵌合抗原受体(Cars)的T细胞能够将MHC非限制性抗体抗原特异性与TCR-z和共刺激信号域偶联，从而触发T细胞的增殖、植入和抗肿瘤活性。尽管如此，为癌症基于细胞的治疗开发的传统基因治疗策略是统一固定的抗原特异性，这意味着只有足够幸运的患者在其癌细胞表面表达处方抗原，才有可能体验到有意义的益处，并且对肿瘤相关抗原表达异质性的肿瘤可能疗效有限。细胞治疗领域仍然受到无法成功开发提供灵活平台的技术的阻碍 产生高度个性化的抗原特异性T细胞，具有强大的效应功能和增强的生存特性，可广泛应用于大多数晚期疾病的治疗。开发一个通用和灵活的平台来产生非MHC限制性抗原特异性T细胞的能力对癌症和慢性病毒感染的过继免疫治疗具有明确和重要的临床意义。我们建立在强大的概念验证结果的基础上，以验证中心假设，即通过创新的平台重新开发，车式治疗可以显着改进并广泛应用于同时或顺序地靶向多种不同的抗原。这延伸到NIH R21探索/开发生物工程研究资助机制下的NIH投资，其中可行性研究的得分为1%，并以其创新性质和强大的体外和临床应用潜力而闻名。现在，我们已经成功地建立了通用免疫受体的可行性，并确定了平台改进的机会，我们现在处于有利地位，可以扩展这些有希望的研究。在这里，我们联合先进抗体开发和基于T细胞的基因工程方面的科学专业知识，提出1)优化通用免疫受体结构，以增加抗体中间结合；2)开发基于抗体的治疗前TAA成像，与重定向T细胞治疗相结合，作为潜在反应的预测因子；以及3)通过免疫受体的再开发和改善肿瘤的穿透性，提高体内的抗肿瘤效果。本文提出的通用免疫受体平台的成功应用是为了通过开发适应性系统来革命性地进行类CAR基因治疗，该系统首次允许通过重定向T细胞来灵活地靶向抗原特异性，并优化T细胞在体内的存活和功能。

DESCRIPTION (provided by applicant): Genetically engineered T lymphocytes have emerged as "off-the-shelf" serial killers capable of recognizing and eradicating solid and hematological cancers in vivo. T cells expressing chimeric antigen receptors (CARs) have the capacity of coupling MHC-unrestricted antibody-based antigen specificity with TCR-z and costimulatory signaling domains for antigen triggered T cell proliferation, engraftment and anti-tumor activity. Still, conventional gene therapy strategies developed for used in cell-based therapy for cancer are uniformly fixed in their antigen specificity, meaning only patients fortunat enough to have the prescribed antigen expressed on the surface of their cancer cells have the potential to experience meaningful benefit and may have limited efficacy in tumors with heterogeneous tumor-associated antigen expression. The cellular therapy field remains hindered by the inability to successfully develop the technology to deliver a flexible platform for the generation of highly personalized antigen-specific T cells with robust effector function and enhanced survival properties that can be widely applied for the treatment of the majority of patients with advanced disease. The capacity to develop a universal and flexible platform for the generation of non-MHC-restricted antigen-specific T cells has clear and significant clinical implications for adoptive immunotherapy of cancer and chronic viral infection. We build upon strong proof-of-concept results to test the central hypothesis that CAR-like therapy can be dramatically improved and widely applied to target multiple and diverse antigens either simultaneously or sequentially through innovative platform re-development. This extends upon NIH investment under the NIH R21 Exploratory/Developmental Bioengineering Research Grant mechanism, where the feasibility study scored in the 1% percentile and was noted for its innovative nature and strong potential for in vitro and clinical applications. Having now successfully established feasibility for universal immune receptors and identified opportunities for platform improvement, we are now well-positioned to extend these promising studies. Here, we unite scientific expertise in advanced antibody development and T cell-based gene engineering to propose 1) to optimize universal immune receptor construction for increased antibody intermediate binding; 2) to develop pre-therapeutic antibody-based imaging of TAA to combine with redirected T cell therapy as a predictor of potential for response; and 3) to improve anti-tumor efficacy in vivo through immune receptor re-development and improved tumor penetrance. Successful application of universal immune receptor platform as proposed here is staged to revolutionize CAR-like gene therapy through development of adaptable systems that allow for the first time flexibility in targeted antigen-specificity by redirected T cells and optiized T cell survival and function in vivo.